US11304968B2 - Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide - Google Patents
Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide Download PDFInfo
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- US11304968B2 US11304968B2 US16/563,620 US201916563620A US11304968B2 US 11304968 B2 US11304968 B2 US 11304968B2 US 201916563620 A US201916563620 A US 201916563620A US 11304968 B2 US11304968 B2 US 11304968B2
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- OMXUSCKHZYSMCV-UHFFFAOYSA-N CCCOc1ccc(-c2oc3cc(OC4OC(C(=O)O)C(O)C(O)C4O)cc(O)c3c(=O)c2O)cc1O Chemical compound CCCOc1ccc(-c2oc3cc(OC4OC(C(=O)O)C(O)C(O)C4O)cc(O)c3c(=O)c2O)cc1O OMXUSCKHZYSMCV-UHFFFAOYSA-N 0.000 description 2
- QIDQMRKOCROOAI-UHFFFAOYSA-N Cc1ccc(-c2oc3cc(OC4OC(C(=O)O)C(O)C(O)C4O)cc(O)c3c(=O)c2O)cc1OCCO Chemical compound Cc1ccc(-c2oc3cc(OC4OC(C(=O)O)C(O)C(O)C4O)cc(O)c3c(=O)c2O)cc1OCCO QIDQMRKOCROOAI-UHFFFAOYSA-N 0.000 description 2
- YVFOPJPCCHDRRP-PXZPFDPPSA-N CCCOc1cc(-c2oc3cc(OCCO)cc(O)c3c(=O)c2O[C@@H]2O[C@H](CO[C@@H]3O[C@@H](C)[C@H](O)[C@@H](O)[C@H]3O)[C@@H](O)[C@H](O)[C@H]2O)ccc1OCCO Chemical compound CCCOc1cc(-c2oc3cc(OCCO)cc(O)c3c(=O)c2O[C@@H]2O[C@H](CO[C@@H]3O[C@@H](C)[C@H](O)[C@@H](O)[C@H]3O)[C@@H](O)[C@H](O)[C@H]2O)ccc1OCCO YVFOPJPCCHDRRP-PXZPFDPPSA-N 0.000 description 1
- OMXUSCKHZYSMCV-CGLGLLIUSA-N CCCOc1ccc(-c2oc3cc(O[C@@H]4O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]4O)cc(O)c3c(=O)c2O)cc1O Chemical compound CCCOc1ccc(-c2oc3cc(O[C@@H]4O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]4O)cc(O)c3c(=O)c2O)cc1O OMXUSCKHZYSMCV-CGLGLLIUSA-N 0.000 description 1
- QIDQMRKOCROOAI-CGLGLLIUSA-N Cc1ccc(-c2oc3cc(O[C@@H]4O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]4O)cc(O)c3c(=O)c2O)cc1OCCO Chemical compound Cc1ccc(-c2oc3cc(O[C@@H]4O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]4O)cc(O)c3c(=O)c2O)cc1OCCO QIDQMRKOCROOAI-CGLGLLIUSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Definitions
- Hydroxyethylrutosides are semi-synthetic molecules that are made by reacting the phytochemical flavonoid rutin with ethylene oxide. See U.S. Pat. No. 3,420,815. Hydroxyethylrutosides have been used in Europe for the past forty years for chronic venous insufficiency and hemorrhoids under the tradenames VENORUTON® and PARAVENTM.
- VENORUTON® The main components of VENORUTON® are 7-monohydroxyethylrutoside (also called MonoHER); 7,4′-dihydroxyethylrutoside; 7,3′,4′-trihydroxyethylrutoside (also called troxerutin); 5,7,3′,4′-tetrahydroxyethylrutoside; and 7,3′,4′-trihydroxyethylquercetin.
- 7-monohydroxyethylrutoside also called MonoHER
- 7,4′-dihydroxyethylrutoside 7,3′,4′-trihydroxyethylrutoside
- troxerutin also called troxerutin
- 7,3′,4′-trihydroxyethylquercetin See Kendall, Br. J. Pharmacol., 1993, 110, 199-206 and van Acker, Br. J. Pharmacol.,
- VENORUTON® is often administered several times a day in pregnant women. Titapant, J. Med. Assoc. Thai, 2001, October 84 (10) 1395-400 (twice daily to pregnant women for hemorrhoids); Wijayanegara, J. Int. Med. Res., 1992 February, 20, 1, 54-60 (97 pregnant women; twice daily); Bergstein, J. Intl. Med. Res., 1975, 3, 189-93 (69 total double blind with pregnant women; 28+ weeks, 3 times daily).
- metabolites of hydroxyethylrutosides are provided herein.
- the compounds can be used for inhibiting norepinephrine metabolism in subjects in need thereof.
- compositions and methods including metabolites of hydroxyethylrutosides are also provided herein.
- compositions comprising a metabolite of a hydroxyethylrutoside, or a pharmaceutically acceptable salt thereof.
- compositions comprising a metabolite of a hydroxyethylrutoside, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
- the present disclosure provides methods of inhibiting norepinephrine metabolism in a subject in need thereof, comprising administering to the subject a compound (e.g., an effective amount of the compound) wherein the compound is a metabolite of a hydroxyethylrutoside, or a pharmaceutically acceptable salt thereof.
- a compound for use in inhibiting norepinephrine metabolism wherein the compound is a metabolite of a hydroxyethylrutoside, or a pharmaceutically acceptable salt thereof.
- use of a metabolite of a hydroxyethylrutoside compound, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting norepinephrine metabolism.
- compositions comprising a hydroxyethylquercetin-O-glucuronide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
- the present disclosure provides methods of inhibiting norepinephrine metabolism in a subject in need thereof, comprising administering to the subject a hydroxyethylquercetin-O-glucuronide, or a pharmaceutically acceptable salt thereof (e.g., an effective amount of a hydroxyethylquercetin-O-glucuronide, or a pharmaceutically acceptable salt thereof).
- a compound for use in inhibiting norepinephrine metabolism wherein the compound is a hydroxyethylquercetin-O-glucuronide, or a pharmaceutically acceptable salt thereof.
- compositions comprising a hydroxyethylquercetin-7-O-glucuronide, or a pharmaceutically acceptable salt thereof.
- compositions comprising a hydroxyethylquercetin-7-O-glucuronide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
- the present disclosure provides methods of inhibiting norepinephrine metabolism in a subject in need thereof, comprising administering to the subject a compound (e.g., an effective amount of the compound) wherein the compound is a hydroxyethylquercetin-7-O-glucuronide, or a pharmaceutically acceptable salt thereof.
- a compound for use in inhibiting norepinephrine metabolism wherein the compound is a hydroxyethylquercetin-7-O-glucuronide, or a pharmaceutically acceptable salt thereof.
- the present disclosure provides methods of inhibiting norepinephrine metabolism in a subject in need thereof, comprising administering to the subject an effective amount of a composition (e.g., a pharmaceutical composition) comprising a metabolite of a hydroxyethylrutoside, or a pharmaceutically acceptable salt thereof.
- a composition e.g., a pharmaceutical composition
- a metabolite of a hydroxyethylrutoside e.g., a pharmaceutical composition
- the composition comprises a hydroxyethylquercetin-7-O-glucuronide, or a pharmaceutically acceptable salt thereof.
- the composition comprises a hydroxyethylquercetin-7-O-glucuronide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
- compositions for use in inhibiting norepinephrine metabolism in a subject in need thereof, wherein the compositions comprise metabolites of hydroxyethylrutosides, or pharmaceutically acceptable salts thereof.
- compositions for use in inhibiting norepinephrine metabolism in a subject in need thereof, wherein the compositions comprise a hydroxyethylquercetin-7-O-glucuronide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
- compositions comprising a compound of Structural Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
- the present disclosure provides methods of inhibiting norepinephrine metabolism in a subject in need thereof, comprising administering to the subject a compound of Structural Formula I, or a pharmaceutically acceptable salt thereof (e.g., an effective amount of the compound). Also provided is a compound for use in inhibiting norepinephrine metabolism, wherein the compound is represented by Structural Formula I, or a pharmaceutically acceptable salt thereof. Also provided is use of a compound of Structural Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting norepinephrine metabolism.
- compositions comprising a compound of Structural Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
- the present disclosure provides methods of inhibiting norepinephrine metabolism in a subject in need thereof, comprising administering to the subject a compound of Structural Formula II, or a pharmaceutically acceptable salt thereof (e.g., an effective amount of the compound). Also provided is a compound for use in inhibiting norepinephrine metabolism, wherein the compound is represented by Structural Formula II, or a pharmaceutically acceptable salt thereof. Also provided is use of a compound of Structural Formula II, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting norepinephrine metabolism.
- a name of a compound may be generated using a chemical naming program (e.g., CHEMDRAW®, version17.0.0.206, PerkinElmer Informatics, Inc.).
- Compounds of the present invention may have asymmetric centers, chiral axes, and/or chiral planes (e.g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and/or as individual diastereomers or enantiomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention, unless otherwise indicated.
- Ethyl is an alkyl substituent derived from ethane (C 2 H 6 ).
- the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety.
- Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids and bases that are compatible with the treatment of subjects.
- Illustrative inorganic bases which form suitable salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium or barium hydroxides.
- Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines, such as methylamine, trimethyl amine and picoline, or ammonia. The selection criteria for the appropriate salt will be known to one skilled in the art.
- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + ((C 1 -C 4 )alkyl) 4 salts.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
- structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
- compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13 C- or 14 C-enriched carbon are within the scope of this invention.
- Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
- Maternal - Fetal Neonatal Medicine, 27, 11, 2014, 1093-8 reported that, in the same data set, there was an overall 20% decrease in birth defects associated with hydroxyethylrutin use, but a slight increase in some particular ear-related birth defects associated with hydroxyethylrutin use in the first trimester.
- Paput, Congenit. Anom. ( Kyoto ), 2011 September, 51, 3, 126-37 also reported ear-related birth defects amongst pregnant women using hydroxyethylrutosides, noted that over half of such cases included use during the second or third months of pregnancy, and concluded that hydroxyethylrutosides are contraindicated for pregnant women during the second and third months. Therefore, it may reasonably be concluded that it is safe to administer hydroxyethylrutosides to pregnant women in the second and third trimesters.
- hydroxyethylrutosides such as troxerutin
- troxerutin may be beneficial to a depressed subject
- the literature reports that troxerutin is associated with a high interindividual variability, whereby disparate individuals process the same troxerutin dose differently so as to end up with distinctly different levels of troxerutin metabolites in their plasma. When this occurs, some members of the group receive a healthy dose, but a significant percentage of the group receive a substantially inadequate dose.
- Interindividual variation is typically represented by calculating the coefficient of variation (COV), which is defined as SD/mean, in which SD is the standard deviation associated with the mean.
- COV coefficient of variation
- SD the standard deviation associated with the mean.
- the COVs associated with hydroxyethylrutosides/troxerutins are about 50%, which would indicate that there is a relatively large amount of interindividual variation associated with their oral delivery in humans.
- flavone glycosides such as troxerutin
- troxerutin flavone glycosides
- Glucuronide flavones appear to absorb in the stomach and upper small intestine.
- scutellarin a flavone glucuronide
- the low pH of stomach favors the neutral species (as the pKa of scutellarin is about 2.7) and absorbability.
- Liu, Zhong Guo Zhong Yao Za Zhi, 2006 June; 31(12):999-1001 reported that baicalin (a flavone glucuronide) preferentially absorbs in the rat stomach. Taiming, J.
- glucuronide flavones appear to absorb in the stomach and upper small intestine, they may substantially avoid the colon and thereby display lower interindividual variation than their corresponding glucoside flavones (like troxerutin).
- a review of the literature indicates that the COVs associated with the oral delivery of flavone glucuronides are substantially less than the COVs associated with hydroxyethylrutosides (which were shown above to be about 50%; Table 1).
- the average human plasma CMax COV associated with oral delivery of scutellarin (a flavone-7-O-glucuronide) is only about 33%, while the human plasma average AUC COV associated with oral delivery of scutellarin is only about 22%.
- the present invention solves the issue of high interindividual variation problems associated with the hydroxyethylrutosides by providing metabolites of the parent molecules in glucuronide form.
- flavone-7-glucuronides are not very water soluble.
- Chen, Cancer Lett. 2014 Nov. 1; 354(1): 5-11 reported that baicalin is poorly soluble in water
- Xiao Eur J Pharm Sci. 2016 Oct. 10; 93:456-67 reported that scutellarin is poorly soluble in water. Therefore, it may reasonably be determined that hydroxyethylquercetin-7-O-glucuronides are likewise poorly soluble in water.
- the hydroxyethylquercetin glucuronide is in the form of a salt, such as a sodium salt.
- the salt can be made by simply mixing stoichiometric amounts of the glucuronide and sodium hydroxide or sodium bicarbonate. It is believed that the salt of the glucuronide will be suitably water soluble, thereby improving the oral bioavailability of the glucuronide.
- the mono -3′-O-hydroxyethylquercetin-glucuronide is in the form of a salt, such as a sodium salt. Therefore, in some aspects, there is provided a pharmaceutical composition comprising a salt comprising hydroxyethylquercetin-7-O-glucuronate and a pharmaceutically acceptable carrier.
- the hydroxyethylquercetin-7-O-glucuronate is a monohydroxyethylquercetin -7-O-glucuronate.
- the present disclosure provides compositions designed to increase stomach absorption of the flavone glucuronide.
- a pH 2 Acid solution e.g., 0.1 N citric acid
- gastric emptying time t1 ⁇ 2
- a method in which about 300 ml of low pH acidic media e.g., 0.1 N citric acid ( ⁇ 6 g per liter); white vinegar (pH 2.4) or lime juice (pH 2-2.5)
- white vinegar pH 2.4
- lime juice pH 2-2.5
- betaine HCl (pH ⁇ 1) can be used as the acidifier.
- One aspect is a compound comprising a metabolite of a hydroxyethylrutoside (e.g., a monohydroxyethylrutoside, a dihydroxyethylrutoside, a trihydroxyethylrutoside), or a pharmaceutically acceptable salt thereof.
- the compound is a metabolite of troxerutin.
- Another aspect is a compound comprising a hydroxyethylquercetin glycoside (e.g., a monohydroxyethylquercetin glycoside, a dihydroxyethylquercetin glycoside, a trihydroxyethylquercetin glycoside), or a pharmaceutically acceptable salt thereof.
- a hydroxyethylquercetin glycoside e.g., a monohydroxyethylquercetin glycoside, a dihydroxyethylquercetin glycoside, a trihydroxyethylquercetin glycoside
- the hydroxyethylquercetin glycoside is a monohydroxyethylquercetin glycoside (e.g., a mono-3′-O-hydroxyethylquercetin glycoside, a mono-4′-O-hydroxyethylquercetin glycoside, a mono-7-O-hydroxyethylquercetin glycoside, a monohydroxyethylquercetin glucuronide).
- Mono-4′-hydroxyethylquercetin glucuronide is available from BOC Sciences, Shirley, N.Y., 11967, as item 483517.
- glycoside refers to a compound comprising a sugar moiety that is attached to the compound via a glycosidic bond.
- glycoside modifies the particular compound described by the name, such that the modified compound includes a sugar moiety that is attached to the compound via a glycosidic bond.
- a sugar moiety of a glycoside can be a monosaccharide or a polysaccharide.
- glycosides include, but are not limited to, glucuronide, glucoside and rutinose.
- the glycoside is a glucuronide.
- the glycoside is a glucoside.
- the hydroxyethylquercetin glycoside is a hydroxyethylquercetin -3-O-glycoside (e.g., a hydroxyethylquercetin-3-O-glucuronide, such as mono -3′-O-hydroxyethylquercetin-3-O-glucuronide or mono-4′-O-hydroxyethylquercetin-3-O-glucuronide).
- a hydroxyethylquercetin-3-O-glycoside e.g., a hydroxyethylquercetin-3-O-glucuronide, such as mono -3′-O-hydroxyethylquercetin-3-O-glucuronide or mono-4′-O-hydroxyethylquercetin-3-O-glucuronide.
- the hydroxyethylquercetin glycoside is a hydroxyethylquercetin-5-O-glycoside (e.g., a hydroxyethylquercetin-5-O-glucuronide, such as mono-3′-O-hydroxyethylquercetin -5-O-glucuronide or mono-4′-O-hydroxyethylquercetin-5-O-glucuronide).
- a hydroxyethylquercetin-5-O-glycoside e.g., a hydroxyethylquercetin-5-O-glucuronide, such as mono-3′-O-hydroxyethylquercetin -5-O-glucuronide or mono-4′-O-hydroxyethylquercetin-5-O-glucuronide.
- the hydroxyethylquercetin glycoside is a hydroxyethylquercetin-7-O-glycoside (e.g., a hydroxyethylquercetin-7-O-glucuronide, such as mono-3′-O-hydroxyethylquercetin -7-O-glucuronide or mono-4′-O-hydroxyethylquercetin-7-O-glucuronide).
- a hydroxyethylquercetin-7-O-glycoside e.g., a hydroxyethylquercetin-7-O-glucuronide, such as mono-3′-O-hydroxyethylquercetin -7-O-glucuronide or mono-4′-O-hydroxyethylquercetin-7-O-glucuronide.
- the hydroxyethylquercetin glycoside is a hydroxyethylquercetin-3′-O-glycoside (e.g., a hydroxyethylquercetin-3′-O-glucuronide, such as mono-7-O-hydroxyethylquercetin -3′-O-glucuronide).
- a hydroxyethylquercetin-3′-O-glycoside e.g., a hydroxyethylquercetin-3′-O-glucuronide, such as mono-7-O-hydroxyethylquercetin -3′-O-glucuronide.
- the hydroxyethylquercetin glycoside is a hydroxyethylquercetin-4′-O-glycoside (e.g., a hydroxyethylquercetin-4′-O-glucuronide, such as mono-7-O-hydroxyethylquercetin -4′-O-glucuronide).
- a hydroxyethylquercetin-4′-O-glycoside e.g., a hydroxyethylquercetin-4′-O-glucuronide, such as mono-7-O-hydroxyethylquercetin -4′-O-glucuronide.
- the glycoside component of mono-3′-O-hydroxyethylquercetin-glycoside is a glucuronide.
- the glucuronide component is a 7-O-glucuronide (thereby producing mono-3′-O-hydroxyethylquercetin-7-O-glucuronide; see Structural Formula I).
- the glycoside component of mono -3′-O-hydroxyethylquercetin-glycoside is a glucoside.
- Mono-3′-hydroxyethylquercetin -7-O-glucuronide is available from Sinco Pharmachem Inc., West Bloomfield Township, Mich.
- One aspect is a compound comprising a hydroxyethylquercetin-7-O-glucuronide, or a pharmaceutically acceptable salt thereof.
- a second aspect is a compound represented by Structural Formula II:
- a third aspect is a compound represented by Structural Formula III:
- a fourth aspect is a compound represented by Structural Formula IV:
- Troxerutin is a compound represented by Structural Formula V:
- compositions comprising one or more compounds disclosed herein (e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin-7-O-glucuronide, a compound of any of Structural Formulas I-IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
- a composition of the invention is formulated for administration to a subject (e.g., a patient) in need of the composition.
- a composition of the invention is formulated for oral, intravenous, subcutaneous, intraperitoneal or dermatological administration to a subject in need thereof.
- a composition of the invention further comprises a second acid.
- the second acid is selected from citric acid, hydrochloric acid, and a combination thereof.
- the glucuronide compounds described herein are acids (i.e., a first acid) in the described compositions, therefore, a second acid can be added to the composition. Without wishing to be bound by any particular theory, it is believed that that the second acid increases gastric residence time of the compound in its protonated (neutral) form when administered.
- pharmaceutically acceptable carrier or excipient refers to a non-toxic carrier or excipient that does not destroy the pharmacological activity of the agent with which it is formulated and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the agent.
- compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- ⁇ -tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropy
- SEDDS self-emulsifying drug delivery systems
- Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives, can also be advantageously used to enhance delivery of agents described herein.
- compositions described herein may be administered by parenterally or non-parenteral means of administration, including, for example, orally, parenterally, by inhalation (e.g., intrabronchial, intranasal or oral inhalation, intranasal drops), topically, rectally, nasally, buccally, vaginally, dietarily, transdermally or via an implanted reservoir.
- inhalation e.g., intrabronchial, intranasal or oral inhalation, intranasal drops
- topically rectally, nasally, buccally, vaginally, dietarily, transdermally or via an implanted reservoir.
- provided compounds or compositions are administrable intravenously and/or intraperitoneally. Administration can be local or systemic as indicated. The preferred mode of administration can vary depending on the particular compound chosen.
- parenteral or “parenterally”, used interchangeably herein, includes injection, subcutaneous, intracutaneous, intravenous, intramuscular, intradermal, intraocular, intravitreal, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques.
- compositions provided herein can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, pills, aqueous suspensions, dispersions and solutions.
- carriers commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried cornstarch.
- the active ingredient can be suspended or dissolved in an oily phase and combined with emulsifying and/or suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
- an oral formulation is formulated for immediate release or sustained/delayed release.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium salts, (g) wetting agents, such as acetyl alcohol and glycerol mono
- compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
- a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.
- excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
- a compound described herein can also be in micro-encapsulated form with one or more excipients.
- the compound can be admixed with at least one inert diluent such as sucrose, lactose or starch.
- inert diluent such as sucrose, lactose or starch.
- dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example, by an outer coating of the formulation on a tablet or capsule.
- a compound described herein can be provided in an extended (or “delayed” or “sustained”) release composition.
- This delayed-release composition comprises the compound in combination with a delayed-release component.
- a delayed-release composition allows targeted release of a provided agent into the lower gastrointestinal tract, for example, into the small intestine, the large intestine, the colon and/or the rectum.
- a delayed-release composition further comprises an enteric or pH-dependent coating, such as cellulose acetate phthalates and other phthalates (e.g., polyvinyl acetate phthalate, methacrylates (Eudragits)).
- the delayed-release composition provides controlled release to the small intestine and/or colon by the provision of pH sensitive methacrylate coatings, pH sensitive polymeric microspheres, or polymers which undergo degradation by hydrolysis.
- the delayed-release composition can be formulated with hydrophobic or gelling excipients or coatings.
- Colonic delivery can further be provided by coatings which are digested by bacterial enzymes such as amylose or pectin, by pH-dependent polymers, by hydrogel plugs swelling with time (Pulsincap), by time-dependent hydrogel coatings and/or by acrylic acid linked to azoaromatic bonds coatings.
- compositions described herein can also be administered in the form of suppositories for rectal administration. These can be prepared by mixing a compound described herein with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug.
- suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
- compositions can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, for example, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
- the compositions can be formulated in an ointment such as petrolatum.
- compositions can also be administered by nasal aerosol or inhalation.
- Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- compositions can be formulated so that a dosage of from about 0.01 mg/kg to about 100 mg/kg body weight/day of the agent can be administered to a subject receiving the composition.
- a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific agent employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician and the severity of the particular disease/disorder being treated.
- the amount of a compound in the composition will also depend upon the particular compound in the composition.
- compositions can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
- This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
- the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- suitable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
- surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
- compositions comprising a compound described herein (e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin-7-O-glucuronide, a compound of any of Structural Formulas I-IV), or a pharmaceutically acceptable salt thereof, can also include one or more other therapeutic agents.
- a compound described herein e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin-7-O-glucuronide, a compound of any of Structural Formulas I-IV
- a pharmaceutically acceptable salt thereof can also include one or more other therapeutic agents.
- the agents should be present at dosage levels of between about 1 to 100%, and more preferably between about 5% to about 95% of the dosage normally administered in a monotherapy regimen.
- the additional agent(s) can be part of a single dosage form, mixed together with the compound described herein, or a pharmaceutically acceptable salt thereof, in a single composition.
- the additional agent(s) can be administered separately, as part of a multiple dose regimen, from the compound described herein, or a pharmaceutically acceptable salt thereof.
- kits comprising a compound described herein (e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin-7-O-glucuronide, a compound of any of Structural Formulas I-IV), or a pharmaceutically acceptable salt thereof, and an additional agent(s) (e.g., a second acid).
- the kit comprises an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to treat a disease, disorder or condition described herein, and an effective amount of an additional agent(s) to treat a disease, disorder or condition described herein.
- compositions described herein can, for example, be administered by any of the methods described herein, including injection, intravenously, intraarterially, intraocularly, intravitreally, subdermally, orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 mg/kg to about 100 mg/kg of body weight or, alternatively, in a dosage ranging from about 1 mg/dose to about 5000 mg/dose or from about 1 mg/dose to about 1,000 mg/dose, every 4 to 120 hours (e.g., about every 24 hours), or according to the requirements of the particular drug. In one embodiment, the dosage is about 450 mg/dose.
- compositions will be administered from about 1 to about 6 (e.g., 1, 2, 3, 4, 5 or 6) times per day or, alternatively, as a continuous infusion.
- amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration.
- a typical preparation will contain from about 5% to about 95% active compound (w/w).
- a preparation can contain from about 20% to about 80% active compound (w/w).
- Doses lower or higher than those recited above may be required.
- Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific agent employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.
- a maintenance dose of a compound e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin-7-O-glucuronide, a compound of any of Structural Formulas I-IV
- a pharmaceutically acceptable salt thereof, composition or combination of this invention can be administered, if necessary.
- the dosage or frequency of administration, or both can be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level.
- Subjects may, however, require intermittent treatment on a long-term basis upon recurrence of disorder symptoms.
- Kienzler Eur. J. Clin. Pharmacol., 2002, 58, 395-402 reported that oral administration of hydroxyethylrutoside-containing VENORUTON® in human volunteers results in detectable plasma levels of two major metabolites—mono-3′-O-hydroxyethyl quercetin-glucuronide (Mono-3′-O-HEQG) and mono-4′-O-hydroxyethylquercetin-glucuronide.
- Mono-3′-O-HEQG is attractive as a monotherapy because i) as a hydroxyethylquercetin-containing compound, it likely has the same beneficial effects as troxerutin and MonoHER upon cortisol, and so may be useful in treating antenatal or postpartum depression, and ii) it has an exceptionally long terminal half-life of at least 17 hours (Kienzler, Eur. J. Clin. Pharmacol., 2002, 58, 395-402 FIG. 2), thereby possibly allowing for only a single administration a day. A single administration per day would represent an improvement in ease of use over the current multiple administrations per day of hydroxyethylrutosides.
- the way to reliably produce Mono-3′-O-HEQG in the blood stream is to avoid having to rely on the liver to produce it from starting materials that do not include molecules solely hydroxylethylated at the 3′ position. Rather, the way to reliably produce the molecule is to administer a rutin-based molecule solely hydroxylethylated at the 3′ position.
- kits for attaining detectable levels of mono-3′-O-hydroxyethylquercetin glucuronide in a subject comprising administering a mono-3′-O-hydroxyethylquercetin-glycoside or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent to the subject.
- methods of reliably attaining detectable levels of Mono-3′-O-HEQG comprising orally administering a composition comprising mono-3′-O-hydroxyethylquercetin and a pharmaceutically acceptable carrier.
- mono-3′-O-hydroxyethylquercetin-glycoside may be cleaved in the colon by colonic microbiota to produce mono-3′-O-hydroxyethylquercetin (Mono-3′-O-HEQ). From there, it is expected that Mono-3′-O-HEQ will travel through the colon wall to the liver where it will be glucuronidated to become mono-3′-O-hydroxyethylquercetin glucuronide again. Jaganath., Free Rad. Biol.
- Hydroxyethylrutosides may be useful in preventing postpartum depression by enhancing norepinephrine levels in the brain. Hydroxyethylrutosides prevent metabolism of norepinephrine, thereby prolonging norepinephrine life (and increasing venous tone). See Araujo, Arch. Int., Pharmacoldyn., Ther., 1985 October, 277, 2, 192-202 (VENORUTON® blocks norepinephrine inactivation). Norepinephrine is associated with alertness. Strahler, Biol Psychol. 2013 September; 94(1):160-6. doi: 10.1016/j.biopsycho.2013.06.002. Epub 2013 Jun.
- a compound described herein e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin -7-O-glucuronide, a compound of any of Structural Formulas I-IV
- a pharmaceutically acceptable salt thereof or a composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
- a compound described herein e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin-7-O-glucuronide, a compound of any of Structural Formulas I-IV
- a pharmaceutically acceptable salt thereof e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin-7-O-glucuronide,
- hydroxyethylrutosides appear to be safe for pregnant women and correct cortisol-related problems; as such, also provided herein are methods of treating perinatal, antenatal (i.e., prenatal) and/or postpartum depression in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin-7-O-glucuronide, a compound of any of Structural Formulas I-IV), or a pharmaceutically acceptable salt thereof, or a composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
- a compound described herein e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin-7-O-glucuronide, a compound of any of Structural Formulas I-IV
- treat and “treatment” refer to therapeutic treatment, wherein the object is to slow down (lessen) an undesired physiological change or disease, or provide a beneficial or desired clinical outcome during treatment.
- beneficial or desired clinical outcomes include alleviation of symptoms, diminishment of extent of disease/disorder, stabilization (i.e., not worsening) of disease/disorder, delay or slowing of disease/disorder progression, amelioration or palliation of the disease/disorder state, and/or remission (whether partial or total), whether detectable or undetectable.
- Those in need of treatment include those subjects already with the undesired physiological change or disease/disorder as well as those subjects prone to have the physiological change or disease/disorder.
- the subject e.g., patient
- a mammal e.g., human, non-human primate, cow, sheep, goat, horse, dog, cat, rabbit, guinea pig, rat, mouse or other bovine, ovine, equine, canine, feline, or rodent organism.
- the subject is a human.
- the subject is a pregnant human.
- the pregnant human is in the second or third trimester.
- the pregnant human is in the third trimester.
- the pregnant human is in the second trimester.
- the subject's pregnancy is at about the 20th to 28th week of gestation.
- the subject is a human that has given birth about 1 to about 4 weeks prior. In one embodiment, the subject is a postnatal human. In some embodiments, the human is postpartum. In some embodiments, the human has given birth no more than about 4 weeks earlier, or the human has given birth no more than about 1 week earlier.
- a “subject in need thereof” refers to a subject who has, or is at risk for developing, a disease or condition described herein (e.g., depression and/or norepinephrine metabolism imbalance).
- a skilled medical professional e.g., physician or clinician
- a “therapeutically effective amount” or “effective amount”, used interchangeably herein, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
- a therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual.
- Example indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient or reduction of symptoms of depression.
- an effective amount of the compound to be administered can be determined by a clinician of ordinary skill using the guidance provided herein and other methods known in the art, and is dependent on several factors including, for example, the particular compound and/or compositions chosen, the subject's age, sensitivity, tolerance to drugs and overall well-being.
- suitable dosages can be from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.01 mg/kg to about 1 mg/kg body weight per treatment. Determining the dosage for a particular agent, subject and disease is well within the abilities of one of skill in the art.
- the dosage does not cause or produces minimal adverse side effects (e.g., immunogenic response, nausea, dizziness, gastric upset, hyperviscosity syndromes, congestive heart failure, stroke, pulmonary edema).
- a compound described herein e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin-7-O-glucuronide, a compound of any of Structural Formulas I-IV), or a pharmaceutically acceptable salt thereof, can be administered in a single dose or as multiple doses, for example, in an order and on a schedule suitable to achieve a desired therapeutic effect (e.g., inhibiting norepinephrine metabolism). Suitable dosages and regimens of administration can be determined by a clinician of ordinary skill.
- the administration of the compounds/compositions of the invention can include administration of an acidifier, such as, e.g., betaine, or a pharmaceutically acceptable salt thereof, or an acidic liquid media.
- the acidic liquid media has a pH of less than about 3.
- the acidic liquid media comprises citric acid, acetic acid, or hydrochloric acid, or a combination of any of the foregoing.
- the acidic liquid media comprises vinegar or a citrus juice, or a combination of the foregoing.
- acids useful herein include hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, oxalic acid, maleic acid, tartaric acid, succinic acid and malonic acid.
- the acidifier or acidic liquid media is provided to increase the gastric residence time of the compound in its protonated form.
- a fasting stomach has a low pH, yielding the desired protonated (neutral) glucuronide form, but will empty water in 15 minutes (Okabe, Brit. J. Anasthesia, 114, 1, 77-82, 2015), thereby allowing only 15 minutes of compound (i.e., glucuronide) exposure in the stomach.
- a fed stomach has a long gastric emptying time (3 hours), but its higher pH yields an undesired anionic glucuronide form that poorly absorbs.
- an acidifier and/or acidic liquid media is provided with the composition to increase the gastric residence time of the glucuronide in its protonated (neutral) form and to increase its solubility.
- a compound described herein e.g., a metabolite of a hydroxyethylrutoside, a hydroxyethylquercetin-7-O-glucuronide, a compound of any of Structural Formulas I-IV), or a pharmaceutically acceptable salt thereof, can also be administered in combination with one or more other therapies or treatments, e.g., additional therapeutic agents.
- the agent is typically administered as a single dose (by, e.g., injection, infusion, orally), followed by repeated doses at particular intervals (e.g., one or more hours) if desired or indicated.
- the compound, or a pharmaceutically acceptable salt thereof can be administered before, after or concurrently with the other therapy (e.g., an additional agent(s)).
- the compound, or a pharmaceutically acceptable salt thereof, and other therapy can be in separate formulations or the same formulation.
- the compound, or a pharmaceutically acceptable salt thereof, and other therapy can be administered sequentially, as separate compositions, within an appropriate time frame as determined by a skilled clinician (e.g., a time sufficient to allow an overlap of the pharmaceutical effects of the therapies).
- the actual dose of a therapeutic agent and treatment regimen can be determined by the physician or clinician, taking into account the nature of the disease, other therapies being given, and subject characteristics.
- a flavone glucuronide pharmaceutical composition comprises:
- Flavone glucuronide 450 mg Gelatin 31 mg Magnesium Stearate 4 mg Microcrystalline cellulose 62 mg Sodium starch glycollate 27 mg Talc 6 mg
- the composition may comprise other flavonoids, such as hesperidin at 50 mg.
- a flavone glucuronate salt pharmaceutical composition comprises:
- Flavone glucuronate salt (as glucuronide) 450 mg Gelatin 31 mg Magnesium Stearate 4 mg Microcrystalline cellulose 62 mg Sodium starch glycollate 27 mg Talc 6 mg
- the composition may comprise other flavonoids, such as hesperidin at 50 mg.
- a hydroxyethylquercetin-7-O-glucuronide pharmaceutical composition comprises:
- the composition may comprise other flavonoids, such as hesperidin at 50 mg.
Abstract
Description
or a pharmaceutically acceptable salt thereof. Also provided are compositions (e.g., pharmaceutical compositions) comprising a compound of Structural Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
or a pharmaceutically acceptable salt thereof. Also provided are compositions (e.g., pharmaceutical compositions) comprising a compound of Structural Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
TABLE 1 |
(hydroxyethylrutoside interindividual variation) |
Cmax | AUC | |
Author | COV | COV |
Kienzler, Eur. J. Clin. Pharmacol., 2002, 58, 395-402 | 41% | 45%, 56% |
Yu, Med. J. Nat. Def. Forces North China, 2006-04 | 49% | 48% |
Yu, supra | 76% | 62% |
Liu, Rapid Comm. Mass Spectro., 2006, 20, 3522-26 | 35% | 56% |
Cui, Chromatographia 73(1-2): 165-169 • January | 41% | 49% |
2011 | ||
Average | 48% | 53% |
TABLE 2 |
(scutellarin interindividual variation) |
Cmax | AUC | |
Author | COV | COV |
Chu, Chinese Pharmacological Bulletin, January 2015 | 36% | 22% |
Chen Drug Metab Dispos. 2006 August; 34(8): 1345-52 | 33 | 33% |
Feng/Yulan, J. Chromotog. B, 830, 2006, 1-5 | 19 | 12 |
Feng/Yulan, supra | 23 | 16 |
Ju, “Det'n of scutellarin . . . ”, January 2005 | 55 | 28 |
Average | 33% | 22% |
-
- a fasting stomach has a low pH, yielding the desired protonated (neutral) glucuronide form but will empty water in only 15 minutes (t½) (Okabe, Brit. J. Anasthesia, 114, 1, 77-82, 2015), thereby allowing only 15 minutes of glucuronide exposure in the stomach;
- a fed stomach has a long gastric emptying time (˜3 hours) but its higher pH yields the undesired anionic glucuronide form that poorly absorbs.
Flavone glucuronide | 450 | mg | ||
Gelatin | 31 | mg | ||
Magnesium Stearate | 4 | mg | ||
Microcrystalline cellulose | 62 | mg | ||
Sodium starch glycollate | 27 | mg | ||
Talc | 6 | mg | ||
Optionally, the composition may comprise other flavonoids, such as hesperidin at 50 mg.
Flavone glucuronate salt (as glucuronide) | 450 | mg | ||
Gelatin | 31 | mg | ||
Magnesium Stearate | 4 | mg | ||
Microcrystalline cellulose | 62 | mg | ||
Sodium starch glycollate | 27 | mg | ||
Talc | 6 | mg | ||
Optionally, the composition may comprise other flavonoids, such as hesperidin at 50 mg.
Hydroxyethylquercetin-7-O-glucuronide | 450 | mg | ||
Gelatin | 31 | mg | ||
Magnesium Stearate | 4 | mg | ||
Microcrystalline cellulose | 62 | mg | ||
Sodium starch glycollate | 27 | mg | ||
Talc | 6 | mg | ||
Optionally, the composition may comprise other flavonoids, such as hesperidin at 50 mg.
Claims (19)
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PCT/IB2019/058343 WO2020070643A1 (en) | 2018-10-02 | 2019-10-01 | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide |
EP19783715.6A EP3860617A1 (en) | 2018-10-02 | 2019-10-01 | Pharmaceutical compositions comprising a hydroxyethylquercetin glucuronide |
JP2021517946A JP2022511400A (en) | 2018-10-02 | 2019-10-01 | Pharmaceutical composition containing hydroxyethyl quercetin glucuronide |
US17/580,954 US20220143058A1 (en) | 2018-11-16 | 2022-01-21 | Pharmaceutical Compositions Comprising a Hydroxyethylquercetin Glucuronide |
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